Medial Frontal Cortex GABA Concentrations in Psychosis Spectrum and Mood Disorders: A Meta-analysis of Proton Magnetic Resonance Spectroscopy Studies

Abstract

Background: Abnormalities of GABAergic (gamma-aminobutyric acidergic) systems may play a role in schizophrenia and mood disorders. Magnetic resonance spectroscopy allows for noninvasive in vivo quantification of GABA; however, studies of GABA in schizophrenia have yielded inconsistent findings. This may stem from grouping together disparate voxels from functionally heterogeneous regions.

Methods: We searched PubMed for magnetic resonance spectroscopy studies of GABA in the medial frontal cortex (MFC) in patients with schizophrenia, bipolar disorder, and depression and in individuals meeting criteria for ultra-high risk for psychosis. Voxel placements were classified as rostral-, rostral-mid-, mid-, or posterior MFC, and meta-analyses were conducted for each group for each subregion.

Results: Of 341 screened articles, 23 studies of schizophrenia, 6 studies of bipolar disorder, 20 studies of depression, and 7 studies of ultra-high risk met the inclusion criteria. Meta-analysis revealed lower mid- (standardized mean difference [SMD] = -0.28, 95% CI, -0.48 to -0.07, p < .01) and posterior (SMD = -0.29, 95% CI, -0.49 to -0.09, p < .01) MFC GABA in schizophrenia and increased rostral MFC GABA in bipolar disorder (SMD = 0.76, 95% CI, 0.25 to -1.25, p < .01). In depression, reduced rostral MFC GABA (SMD = -0.36, 95% CI, -0.64 to -0.08, p = .01) did not survive correction for multiple comparisons. We found no evidence for GABA differences in individuals at ultra-high risk for psychosis.

Conclusions: While limited by small numbers of published studies, these results substantiate the relevance of GABA in the pathophysiology of psychosis spectrum and mood disorders and underline the importance of voxel placement.

Keywords: (1)H-MRS; Bipolar disorder; GABA; Schizophrenia; Ultra-high risk.

Figure 1:

PRISMA flow diagram of search for meta-analyses. Note, two studies included both schizophrenia and ultra-high risk samples, and so the breakdown of included studies totals 56 due to these duplicates.

Figure 2:

Voxel location in medial frontal cortex GABA ¹H-MRS studies. A: ¹H-MRS studies of schizophrenia; B: ¹H-MRS studies of depression; C: ¹H-MRS studies of bipolar disorder; and D: ¹H-MRS studies of individuals meeting ultra-high risk of developing psychosis criteria.

Figure 3:

Forest plots showing summary effect sizes for group differences between individuals with schizophrenia and healthy controls in the A) rostral MFC; B) rostral-mid MFC, C) mid MFC and D) posterior MFC. Negative SMDs denote lower GABA concentrations in patients than healthy controls; positive SMDs denote higher GABA concentrations in patients than healthy controls. Abbreviations: SMD – standardized mean difference, CI – confidence interval, RE – Random effects, df – degrees of freedom.

Figure 4:

Forest plots showing summary effect sizes for group differences between individuals with depression and healthy controls in the A) rostral MFC, B) rostral-mid MFC and C, mid MFC. Negative SMDs denote lower GABA concentrations in patients than healthy controls; positive SMDs denote higher GABA concentrations in patients than healthy controls. Abbreviations: SMD – standardized mean difference, CI – confidence interval, RE – Random effects, df – degrees of freedom.

Figure 5:

Forest plots showing summary effect sizes for group differences between individuals with bipolar disorder and healthy controls in the A) rostral MFC, and B) mid MFC, and individuals meeting ultra-high risk for psychosis criteria and healthy controls in the C) rostral MFC, D) mid MFC and E) posterior MFC. Negative SMDs denote lower GABA concentrations in patients than healthy controls, positive SMDs denote higher GABA concentrations in patients than healthy controls. Abbreviations: SMD – standardized mean difference, CI – confidence interval, RE – Random effects, df – degrees of freedom.